Hepatotoxic drugs

Furst, S.M., Chen, M. and Gandolfi, A.J., Use of halothane as a model for investigating chemical-induced autoimmune hepatotoxicity, Drug Info. J., 30, 301, 1996. 

Curtis LR, Mehendale HM. 1980. Specificity of chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity. Drug Metab Dispos 8 23-27. 

Hepatotoxicity Hepatotoxicity, primarily of the hepatocellular type, has been associated with ketoconazole, including rare fatalities. Measure liver function before starting treatment and frequently during treatment. Monitor patients receiving ketoconazole concurrently with other potentially hepatotoxic drugs, particularly those patients requiring prolonged therapy or those with a history of liver disease. 

Hepatic disease Use with caution in patients with hepatic disease or in conjunction with hepatotoxic drugs. 

Second, it must be able to detect chronic as well as acute toxicities, especially as it is the former that is the more common cause of safety attrition in the clinics. It is critical that cells be exposed to toxicants for sufficient time to allow expression of the cytotoxicity [6, 11, 14—16]. Three days of incubation of cells was effective for more than 95% human hepatotoxic drugs, whereas a single day of incubation was frequently ineffective [4] or produced cytotoxicity at a much higher concentration [4, 11, 14]. 

Figure 15.1 Compilation of structural alerts/toxicophores known to undergo bioactivation and examples of hepatotoxic drugs containing the structural alerts.

Obach, R. S., Kalgutkar, A. S., Soglia, J. R., and Zhao, S. X. (2008). Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from non-hepatotoxic drugs An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem. Res. Toxicol. 21 1814-1822. 

James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos. 2003 31 1499-1506. 

Concomitant administration of paracetamol with other hepatotoxic drugs or drugs acting on liver microsomal enzymes enhances paracetamol toxicity. Other drugs that interact with paracetamol are metoclopramide, probenecid, and cholestyramine.81... 

Valproate Care must be exercised when administering valproate with aspirin, warfarin, or other hepatotoxic drugs. 

Rikans LE. 1987. The oxidation of acrolein by rat liver aldehyde dehydrogenases. Relation to allyl alcohol hepatotoxicity. Drug Metab Dispos 15 356-362. 

Classification of chemically induced hepatotoxicity is primarily based upon pattern of incidence and histopathological morphology. Intrinsic hepatotoxic drugs demonstrate a broad incidence, dose-response relationship and will usually give similar results in humans and experimental animals. The incidence of liver damage from idiosyncratic hepatotoxicants is limited to susceptible individuals and results from hypersensitivity reactions or unusual metabolic conversions that can occur due to polymorphisms in drug metabolism genes (see Chapters 11 and 13). 

Polypharmacy For example, NSAIDs if used with other hepatotoxic drugs increase the risk of hepatotoxicity. Isoniazid with rifampicin or pyrazinamide... 

Echinacea 1. Hepatotoxic drugs, e.g. anabolic steroids 2. amiodarone 3. Methotrexate 4. Ketoconazole Risk of additive hepatotoxicity Use of echinacea for over 8 weeks can cause hepatotoxicity Be aware and use drugs with a potential to cause hypertonicity cautiously, monitoring clinically and biochemically for any early signs of hepatic dysfunction... 

There are a number of causes including (I.) well-known hepatotoxic factors (e.g. superimposed viral infection, alcohol consumption, hepatotoxic drugs, intoxication) and (2.) endogenous factors (e.g. sepsis, variceal bleeding, gastrointestinal haemorrhage, diarrhoea, hypoxia). Acute liver failure is frequently the result of a chain of damaging events, like a vicious circle. 

There are mild to moderate increases in liver transaminases during treatment with rifampicin plus isoniazid in most patients. However, biochemical hepatitis is diagnosed when transaminase activities increase to more than four times the upper limit of the reference ranges on two occasions at least 1 week apart, or more than five times on any single occasion. This calls for withdrawal of all potentially hepatotoxic drugs (rifampicin, isoniazid, and pyrazinamide) until the enzymes return to the reference ranges. During this period, streptomycin plus etham-butol, with or without cycloserine and a fluoroquinolone, is recommended in seriously ill patients. 

One of the most important predictors of hepatotoxicity during antituberculosis drug therapy is an abnormal hver function test at basehne. It is reasonable to avoid potentially hepatotoxic drugs in the management of patients with pre-existing hver disease. 

Most patients who receive asparaginase develop hver function abnormalities, which can be fatal (12). This adverse effect is of major concern in patients who are also taking other hepatotoxic drugs, such as methotrexate and mercaptopurine. Jaundice and increased serum bihr-ubin and transaminases occur often, and hepatomegaly and fatty deposits occur occasionally. 

Although the patient took other potentially hepatotoxic drugs, the time-course suggested that infliximab was the... 

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